This invention relates to C-glucosyl ether lipids, including their synthesis and use.
The study of C-glycoside analogs of bioactive O- and N-glycosides is a mature field. In addition to the focus on their structural and conformational properties as probes for the importance of the anomeric and exo-anomeric effects, the significance of C-glycosides is that they are essentially inert to degradation because the anomeric carbon has been transformed from a hydrolytically labile O- or N-acetal link to an ether linkage. The underlying assumption for the use of C-glycoside analogs in glycobiology is that the conformational differences between the O- (or N)-linked natural material and the C-linked analog will be minimal. The corollary to the minimal difference hypothesis is that the recognition and binding of the C-analog will be similar to that of the natural material.
In contrast to the large number of C-glycosides that have been synthesized, there have been surprisingly few direct O vs. C biological activity comparisons. The most thorough comparison was done for the C-lactose O-lactose case reported in significant papers in 1995, 1996, and 1998 by the Kishi and Schmidt and Jiminez-Barbero groups, who focus on nuclear Overhauser enhancement data and modeling results. There is partial but not complete agreement as to the similarities and differences in the conformation of ground-state and of binding conformations. Espinosa, et al., J. Am. Chem. Soc., 118:10862-10871 (1996); Espinosa, et al., J. Am. Chem. Soc., 120:1309-1318 (1998); Wei, et al., J. Org. Chem., 60:2160-2169 (1995); Ravishankar, et al., J. Am. Chem. Soc., 120:11297-11303 (1998). Recently, we reported a comparison between an antiproliferative 2-deoxyglucosyl glycerolipid (compound 1) and its exact C-analog (compound 2) where the C-glycoside showed a several fold weaker activity. Yang, et al., Org. Let., 1:2149-2151 (1999). 
Although C-glycosylamino compounds have been prepared (Gaurat, et al., Tetrahedron Lett., 41:1187-1189 (2000)), there has been no previous preparation of a lipid that is coupled to a C-glycoside in which glucosamine is the parent carbohydrate. It is also noted that direct methods for making C-glycosides having 2-amino groups are recognized as being especially difficult to achieve xe2x80x9cbecause of the incompatibility of neighboring nitrogen-based functional groups . . . with common glycosylation strategiesxe2x80x9d (Bertozzi et al., J. Org. Chem. 1996, 61, 6442-6445).
Briefly, the invention relates to a C-glucosyl ether lipid of the following formula: 
wherein R1 is a C12-C20 alkyl or C12-C20 alkenyl; R2 is a C1-C3 alkyl or a C3 cycloalkyl; and nitrogen containing group. R1 is preferably C16H33 or C18H37, R2 is preferably a C1-C3 is preferably NH2, NHCOR3 or NHSO2R4, wherein R3 is a C1-C3 alkyl, and R4 is a C1-C3 alkyl phenyl, a substituted phenyl or a substituted naphthyl. More preferably, X is NH2, R1 is C16H33 and R2 is CH3. The invention also relates to a pharmaceutical composition containing the C-glucosyl ether lipid defined in the formula, as well as a method of treating an animal afflicted with cancer by administering a anti-cancer effective amount of the pharmaceutical composition.
The invention likewise relates to a method of synthesizing C-glucosyl ether involving a) synthesizing an ether lipid having an sn-2 carbon and an O-alkyl or O-cycloalkyl side chain attached to the sn-2 carbon; b) sulfur-linking a glucose derivative to the ether lipid synthesized in step a) to form a thioglycoside intermediate, the glucose derivative having a nitrogen containing group at the C2 position; and c) converting the thioglycoside intermediate to a C-glucosyl ether lipid via a Ramberg-Bxc3xa4cklund rearrangement.